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Bavdegalutamide (ARV110; ARV-110) is an orally bioavailable PROTAC-based Androgen Receptor (AR) degrader (DC₅₀ = ~1 nM) with potential anticancer activity. May be used for the treatment of metastatic castration-resistant prostate cancer (mCRPC).
| Targets |
Androgen receptor (AR)-targeting PROTAC; Androgen receptor (AR) (DC₅₀ = ~1 nM for degradation in cell-based assays) [2]
Bavdegalutamide (ARV-110) selectively degrades the androgen receptor (AR) via proteolysis-targeting chimera (PROTAC) technology, recruiting E3 ubiquitin ligase to ubiquitinate AR for proteasomal degradation. It shows activity against wild-type AR and clinically relevant mutants (e.g., F876L, T877A, M896V, H874Y). |
|---|---|
| ln Vitro |
In all examined cell lines, bavdegalutamide totally destroys AR, with a 50% degradation concentration (DC50) of less than 1 nM [1]. In LNCaP cells, bavdegalutamide (0.01 nM-300 nM) degrades AR in a dose-dependent manner [1]. The degradation of AR in VCaP cells is caused in a time-dependent manner by bavdegalutamide (10 nM; 0.5-24 hours) [2]. At low nanomolar doses, bavdegalutamide (10-1000 nM) causes apoptosis, suppresses AR-dependent cell growth, and inhibits the production of the AR target gene PSA [2]. In the hyperandrogenic milieu of VCaP cells (R1881, 100 nM), bavdegalutamide (0.01 nM-100 nM) degrades clinically relevant mutant AR proteins (WT AR, F876L, T877A, M896V, and H874V) while maintaining its activity [2].
- AR Degradation: Bavdegalutamide (ARV-110) potently degraded AR in multiple prostate cancer cell lines (e.g., VCaP, LNCaP), with a DC₅₀ of ~1 nM. Degradation was confirmed by Western blot analysis, showing >95% reduction in AR protein levels after 24-hour treatment [2] - Antiproliferative Activity: In VCaP cells, Bavdegalutamide inhibited cell proliferation with an IC₅₀ of 0.3 nM, which correlated with AR degradation and suppression of AR-target gene PSA expression [2] - Apoptosis Induction: Treatment with Bavdegalutamide (10 nM) induced caspase-3/7 activation and Annexin V staining in AR-dependent cell lines, indicating apoptotic cell death [2] Bavdegalutamide induces near-complete AR degradation across all tested cell lines, with a DC50 < 1 nM. In LNCaP cells, AR degradation occurs in a dose-dependent manner (0.01–300 nM). In VCaP cells, treatment with 10 nM Bavdegalutamide for 0.5–24 hours degrades AR time-dependently. At 10–1000 nM, it suppresses AR target gene expression (e.g., PSA), inhibits AR-dependent proliferation, and induces potent apoptosis. Bavdegalutamide retains activity in high-androgen environments (100 nM R1881) and degrades mutant AR proteins (T878A, H875Y) associated with clinical resistance to enzalutamide. |
| ln Vivo |
Bavdegalutamide (oral gavage; 1 mg/kg; QD) displays better than 90% breakdown of AR in vivo. Bavdegalutamide also revealed strong inhibitory effects on tumor growth and AR signaling in LNCaP, VCaP, and prostate cancer patient-derived xenograft (PDX) models [2]. Bavdegalutamide (oral gavage; 3 or 10 mpk; 30 days) demonstrated in vivo effectiveness and decrease in AR target gene expression in a long-term, castrated, enzalutamide-resistant VCaP tumor model. The TGIs for the 3 mpk and 10 mpk dosages were 70% and 60%, respectively. respectively[2].
- Tumor Growth Inhibition: Oral administration of Bavdegalutamide (1 mg/kg daily) in nude mice bearing VCaP xenografts resulted in >90% AR degradation in tumor tissues and significant tumor growth inhibition. After 21 days, treated tumors were 60% smaller than vehicle controls [2] - Enzalutamide-Resistant Models: In a castrate-resistant VCaP xenograft model, Bavdegalutamide (5 mg/kg daily) showed sustained AR degradation and reduced tumor volume by 70% compared to enzalutamide (20 mg/kg) [2] At 1 mg/kg oral daily dosing, Bavdegalutamide achieves >90% AR degradation in xenograft models. Significant tumor growth inhibition (TGI) and suppression of AR signaling are observed in LNCaP, VCaP, and patient-derived xenograft (PDX) models in both intact and castrate settings. In a long-term, castrate, enzalutamide-resistant VCaP model, Bavdegalutamide (3 mg/kg and 10 mg/kg orally for 30 days) reduces tumor growth by 70% and 60%, respectively, and downregulates oncogenic Erg protein expression. |
| Cell Assay |
The Androgen Receptor (AR) remains the principal driver of castration-resistant prostate cancer during the transition from a localized to metastatic disease. Most patients initially respond to inhibitors of the AR pathway, but the response is often short-lived. The majority of patients progressing on enzalutamide or abiraterone exhibit genetic alterations in the AR locus, either in the form of amplifications or point mutations in the AR gene. Given these mechanisms of resistance, our goal is to eliminate the AR protein using the PROteolysis TArgeting Chimera (PROTAC) technology. Here we report an orally bioavailable small molecule ARV-110 that leads to ubiquitination and degradation of AR. ARV-110 completely degrades AR in all cell lines tested, with an observed 50% degradation concentration (DC50) < 1 nM. PROTAC-mediated AR degradation suppresses the expression of the AR-target genes PSA and FKBP5, inhibits AR-dependent cell proliferation, and induces potent apoptosis in VCaP cells. ARV-110 degrades clinically relevant mutant AR proteins and retains activity in a high androgen environment[1].
AR Degradation Assay: Cells (e.g., LNCaP, VCaP) were treated with Bavdegalutamide for 24 hours. AR protein levels were quantified via Western blotting, with DC50 calculated from dose-response curves. Apoptosis and Proliferation: VCaP cells were exposed to 10–1000 nM Bavdegalutamide for 72 hours. Apoptosis was measured by caspase activation assays, and proliferation was assessed via ATP-based luminescence or cell counting. Gene Expression Analysis: After treatment with Bavdegalutamide , RNA was extracted for qPCR to evaluate AR target genes (PSA, FKBP5). |
| Animal Protocol |
In mouse xenograft studies, greater than 90% AR degradation is observed at a 1 mg/kg PO QD dose. Significant inhibition of tumor growth and AR signaling can be achieved in both an intact and castrate setting. Further, ARV-110 demonstrates in vivo efficacy and reduction of oncogenic Erg protein in a long term, castrate, enzalutamide-resistant VCaP tumor model. DMPK and exploratory toxicology studies show robust oral, dose proportional drug exposure in rodent and non-rodent species. In summary, we report preclinical data on ARV-110, an orally bioavailable androgen receptor PROTAC degrader that demonstrates efficacy in enzalutamide-resistant prostate cancer.[1]
In mouse xenograft studies, greater than 90% AR degradation is observed at a 1 mg/kg PO QD dose. Significant inhibition of tumor growth and AR signaling has been achieved in LNCaP, VCaP and prostate cancer patient derived xenograft (PDX) models. Notably, ARV-110 demonstrates in vivo efficacy and reduction of AR-target gene expression in a long term, castrate, enzalutamide-resistant VCaP tumor model.[2] Efficacy Studies: Mice bearing LNCaP, VCaP, or PDX tumors were orally administered Bavdegalutamide (1–10 mg/kg) once daily. Tumor volume was measured weekly, and AR degradation in tumors was confirmed by immunohistochemistry or Western blotting. |
| ADME/Pharmacokinetics |
- Oral Bioavailability: In mice, Bavdegalutamide demonstrated moderate oral bioavailability, with plasma Cₘₐₓ of 2.1 μM and T₁/₂ of 4.2 hours after a 5 mg/kg dose [2]
- Metabolic Stability: The compound showed high stability in human hepatic microsomes (half-life >2 hours at 1 μM), with minimal phase I metabolism [2] |
| Toxicity/Toxicokinetics |
In a Phase 1/2 trial (n=173), no grade ≥4 treatment-related adverse events (TRAEs) occurred at the RP2D (420 mg QD). Common TRAEs included nausea (42%), fatigue (27%), vomiting (23%), diarrhea (15%), and alopecia (11%). Most events were Grade 1–2.
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| References | |
| Additional Infomation |
Bavdegalutamide is an orally available selective androgen receptor (AR)-targeted protein degrader, using the proteolysis targeting chimera (PROTAC) technology, with potential antineoplastic activity. Bavdegalutamide is composed of an AR ligand attached to an E3 ligase recognition moiety. Upon oral administration, bavdegalutamide targets and binds to the AR ligand binding domain. E3 ligase is recruited to the AR by the E3 ligase recognition moiety and the AR target protein is tagged by ubiquitin. This causes ubiquitination and degradation of AR by the proteasome. This prevents the expression of AR target genes and halts AR-mediated signaling. This results in an inhibition of proliferation in AR-overexpressing tumor cells. In addition, the degradation of the AR protein releases the ARV-110 is released and can bind to additional AR target proteins. AR plays a key role in the proliferation of castration-resistant prostate cancer cells (CRPC).
- Mechanism of Action: Bavdegalutamide acts as a PROTAC, recruiting cereblon (CRBN) E3 ligase to induce AR ubiquitination and proteasomal degradation. This mechanism bypasses AR mutations that confer resistance to traditional antagonists [2] - Clinical Development: Bavdegalutamide completed a phase I trial (NCT03888612) in mCRPC patients, with 46% of AR T878X/H875Y mutation-positive patients achieving ≥50% PSA decline. The RP2D was established as 420 mg once daily [2] Bavdegalutamide is the first PROTAC degrader to enter clinical trials (NCT03888612). It targets mCRPC patients resistant to enzalutamide/abiraterone, with enhanced efficacy in those harboring AR T878X/H875Y mutations (PSA50 response: 46%). Molecular weight: 812.29 g/mol; CAS: 2222112-77-6. |
| Molecular Formula |
C41H43CLFN9O6
|
|---|---|
| Molecular Weight |
812.2882
|
| Exact Mass |
811.3
|
| Elemental Analysis |
C, 60.62; H, 5.34; Cl, 4.36; F, 2.34; N, 15.52; O, 11.82
|
| CAS # |
2222112-77-6
|
| PubChem CID |
134414307
|
| Appearance |
Light yellow to yellow solid powder
|
| LogP |
3.9
|
| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
13
|
| Rotatable Bond Count |
9
|
| Heavy Atom Count |
58
|
| Complexity |
1590
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
ClC1=C(C#N)C([H])=C([H])C(=C1[H])OC1([H])C([H])([H])C([H])([H])C([H])(C([H])([H])C1([H])[H])N([H])C(C1C([H])=C([H])C(=NN=1)N1C([H])([H])C([H])([H])C([H])(C([H])([H])C1([H])[H])C([H])([H])N1C([H])([H])C([H])([H])N(C2=C(C([H])=C3C(N(C(C3=C2[H])=O)C2([H])C(N([H])C(C([H])([H])C2([H])[H])=O)=O)=O)F)C([H])([H])C1([H])[H])=O
|
| InChi Key |
CLCTZVRHDOAUGJ-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C41H43ClFN9O6/c42-31-19-28(4-1-25(31)22-44)58-27-5-2-26(3-6-27)45-38(54)33-7-9-36(48-47-33)51-13-11-24(12-14-51)23-49-15-17-50(18-16-49)35-21-30-29(20-32(35)43)40(56)52(41(30)57)34-8-10-37(53)46-39(34)55/h1,4,7,9,19-21,24,26-27,34H,2-3,5-6,8,10-18,23H2,(H,45,54)(H,46,53,55)
|
| Chemical Name |
N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]-6-[4-[[4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl]piperazin-1-yl]methyl]piperidin-1-yl]pyridazine-3-carboxamide
|
| Synonyms |
ARV-110; ARV 110; ARV110; ARV-110; 3-Pyridazinecarboxamide, N-[trans-4-(3-chloro-4-cyanophenoxy)cyclohexyl]-6-[4-[[4-[2-(2,6-dioxo-3-piperidinyl)-6-fluoro-2,3-dihydro-1,3-dioxo-1H-isoindol-5-yl]-1-piperazinyl]methyl]-1-piperidinyl]-; ARV110; N-(trans-4-(3-Chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide; Bavdegalutamide [INN]; Bavdegalutamide [USAN];
Bavdegalutamide;
|
| HS Tariff Code |
2934.99.9001
|
| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
DMSO : ~26.67 mg/mL (~32.83 mM)
|
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 0.79 mg/mL (0.97 mM) (saturation unknown) in 10% DMSO + 40% PEG300 +5% Tween-80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 7.9 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 + to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 10 mg/mL (12.31 mM) in 50% PEG300 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication (<60°C). Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.2311 mL | 6.1554 mL | 12.3109 mL | |
| 5 mM | 0.2462 mL | 1.2311 mL | 2.4622 mL | |
| 10 mM | 0.1231 mL | 0.6155 mL | 1.2311 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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